This Program Project consists of three closely related and integrated proposals focusing on signals which regulate skeletal morphogenesis during embryonic development. Because the same regulatory network is utilized postnatally as the skeleton grows, remodels and repairs itself, these studies will also increase understanding of medically relevant aspects of bone physiology. The projects are highly coordinated, founded in the last 5 years of a highly successful Program Project and a long history of collaborative efforts before that. A unique feature of this team is the exchange of expertise between laboratories whose primary focus has been either developmental biology (Tabin and McMahon) or bone biology (Kronenberg). By continuing the high-resolution histology core and establishing a new core for high-throughput gene expression analysis, the technical capabilities of each individual lab will be extended. All three projects are focused on dissecting the roles of key signaling molecules in skeletal development. Project I will examine the role of PTHrP in chondrogenesis and the role of PTHrP in osteogenesis. Project II will explore the role of Ihh/Shh and Wnt signaling in osteogenesis, and will also develop a fate map of craniofacial skeletogenesis based on a unique code of Fox genes which are suggested to underlie the specification of distinct facial primordia. Project III will study the roles of BMP signaling in chondrogenesis and osteogenesis and will also define the molecular characteristics of the cell types and intercellular signals leading to craniofacial dermal bone formation. These projects are knit together by common themes, complimentary approaches, shared reagents, and direct collaborations. Together these highly related projects will achieve a new level of understanding of the regulation of bone morphogenesis which could not be attained by independent efforts.